Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes

Abstract

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not -at least in liver and muscle -cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10 13 mol/l, a doserelated increase of the -[U-14 C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10 11 mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.

Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

“…The present study demonstrated that the beneficial effects of exendin-4 were also found in CaMTg diabetic mice, and that its major effect was to maintain the b-cell mass, because 1) the exendin-4 treatment increased the insulin contents of the pancreas and islets and 2) it also expanded the insulin-positive area in both nTg and CaMTg mice. Although the extrapancreatic effects of GLP-1 have been reported to participate in the hypoglycemic effects of exendin-4 (Egan et al 1994, Luque et al 2002, Dardevet et al 2004), we could not find any effect of the treatment on plasma glucose levels in the insulin tolerance test.…”

The Physiology of Glucagon-like Peptide 1

“…Nevertheless, in studies involving direct determination of lipolysis rates in human subcutaneous tissue, Bertin et al (16) were unable to find any effects of GLP-1. GLP-1 receptors have also been claimed to be present in rat skeletal muscle (49), and GLP-1 was reported to stimulate glucose metabolism in human myocytes (173). Similar observations were made in studies of L6 myotubes, and there was evidence that the effects were transmitted via receptors distinct from the classical GLP-1 receptor (336).…”

Role of Endogenous Glucagon-Like Peptide-1 in Islet Regeneration After Partial Pancreatectomy

“…On this basis, Ex9-39 is considered to be an inverse agonist of the GLP-1 receptor (26). In contrast, in some studies Ex9-39 does not antagonize GLP-1 action or may even behave as an agonist (27)(28)(29)(30). These observations raise the possibility that although Ex9-39 effectively antagonized the incretin effect of endogenous GLP-1, the growth-promoting effect was not antagonized.…”